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WO1994021293A1 - Procede de traitement de tumeurs a l'aide d'un anticorps apte a se lier a la tenascine - Google Patents

Procede de traitement de tumeurs a l'aide d'un anticorps apte a se lier a la tenascine Download PDF

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Publication number
WO1994021293A1
WO1994021293A1 PCT/US1994/002703 US9402703W WO9421293A1 WO 1994021293 A1 WO1994021293 A1 WO 1994021293A1 US 9402703 W US9402703 W US 9402703W WO 9421293 A1 WO9421293 A1 WO 9421293A1
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WIPO (PCT)
Prior art keywords
antibody
tumor
cystic
coupled
brain
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PCT/US1994/002703
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English (en)
Inventor
Darell D. Bigner
Michael Zalutsky
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Duke University
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Priority to AU64458/94A priority Critical patent/AU6445894A/en
Publication of WO1994021293A1 publication Critical patent/WO1994021293A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A61K51/1066—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from skin

Definitions

  • the present invention relates to the treatment of cancer, and particularly relates to the treatment of cystic brain tumors and cystic brain tumor resection cavities with anti-tenascin antibodies such as 81C6.
  • CNS tumor the glioblastoma multiforme
  • the outlook is somewhat better for less common tumors such as anaplastic astrocytoma and medulloblastoma, but most primary anaplastic CNS tumors are highly resistant to currently available therapy.
  • a first aspect of the present invention is a method of treating a cystic brain tumor.
  • the method comprises administering to a human subject afflicted with a cystic brain tumor (e.g., one which expresses tenascin) an antibody that binds to tenascin in a therapeutically effective amount.
  • the administering step is carried out by depositing the antibody in the cyst cavity of the cystic brain tumor.
  • Also disclosed herein is a method of treating a solid tumor which comprises, first, removing a solid tumor (e.g., one which expresses tenascin) from a solid tissue organ (e.g., the brain) of an afflicted human subject; then forming an enclosed resection cavity in the organ of the subject at the location from which the solid tumor was removed; and then administering to the subject an antineoplastic agent such as an antibody (e.g., an antibody that binds to tenascin) which is selectively toxic to the cells of the solid tumor in a therapeutically effective amount.
  • the administering step is carried out by depositing the antineoplastic agent in the resection cavity.
  • monoclonal antibody 81C6 and antibodies which bind to the epitope bound by monoclonal antibody 81C6.
  • a further aspect of the present invention is the use of an antibody that binds to tenascin as described herein for the preparation of a medicament for carrying out the treatments described herein.
  • Figure 1 shows the survival of three human patients treated by the method of the present invention, as compared to the survival curve of a pooled sample of 383 patients treated by previous methods.
  • Figure 2 shows the nucleotide sequence of 81C6 heavy (Fig. 2A) (SEQ ID N0:1) and light (Fig. 2B) (SEQ ID NO:3) chain variable region genes.
  • the nucleotide sequence is numbered in the righthand margin. Nucleotides with asterisks indicate the conserved octanucleotides.
  • the deduced amino acid sequence is above the nucleotide sequence (SEQ ID NO:3 and SEQ ID NO:4) .
  • Superscript numbers above the amino acid sequence delineate the leader sequence (-20, -4) and the beginning of the actual immunoglobulin sequence (+1) .
  • Underlined amino acids indicate where sequence data were obtained by N-terminal amino acid sequencing.
  • Amino acid sequences disclosed herein are presented in the amino to carboxy direction, from left to right . The amino and carboxy groups are not presented in the sequence. Nucleotide sequences are presented herein by single strand only, in the 5' to 3 ' direction, from left to right. A. Antibodies
  • antibodies refers to all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE.
  • immunoglobulin includes the subtypes of these immunoglobulins, such as IgG ! , -*-g G 2 ' !g G 3 I9 G 4 etc. Of these immunoglobulins, IgM and IgG are preferred, and IgG is particularly preferred.
  • the antibodies may be of any species of origin, including (for example) mouse, rat, rabbit, horse, or human, or may be chimeric antibodies. See, e . g. , M. Walker et al . , Molec . Immunol .
  • Such monoclonal antibodies are produced in accordance with known techniques.
  • the term "antibody” as used herein includes antibody fragments which retain the capability of binding to a target antigen, for example, Fab, F(ab') 2 . and Fv fragments, and the corresponding fragments obtained from antibodies other than IgG. Such fragments are also produced by known techniques.
  • the monoclonal antibodies may be recombinant monoclonal antibodies produced according to the methods disclosed in Reading U.S. Patent No. 4,474,893, or Cabilly et al . , U.S. Patent No. 4,816,567.
  • the antibodies may also be chemically constructed by specific antibodies made according to the method disclosed in Segel et al . , U.S.
  • Monoclonal antibodies may be chimeric antibodies produced in accordance with known techniques.
  • chimeric monoclonal antibodies may be complementarity determining region- grafted antibodies (or "CDR-grafted antibodies”) produced in accordance with known techniques.
  • Monoclonal Fab fragments may be produced in Escherichia coli by recombinant techniques known to those skilled in the art. See, e . g. , W. Huse, Science 246, 1275-81 (1989) .
  • antibodies employed in carrying out the present invention are those which bind to tenascin.
  • Particularly preferred are monoclonal antibody 81C6 and antibodies that bind to the epitope bound by monoclonal antibody 81C6 (i.e., antibodies that cross-react with, or block the binding of, monoclonal antibody 81C6) .
  • the monoclonal antibody 81C6 is a murine IgG2b monoclonal antibody raised from a hybridoma fusion following immunization of BALB/c mice with the glial fibrillary acidic protein (GFAP) - expressing permanent humanglioma line U-251 MG, as known and described in M. Bourdon et al . , Cancer Res . 43, 2796 (1983) .
  • GFAP glial fibrillary acidic protein
  • Monoclonal antibodies used for therapy may be monoclonal antibodies per se or monoclonal antibodies coupled to a therapeutic agent. Such antibodies are sometimes referred to herein as therapeutic monoclonal antibodies. Any therapeutic agent conventionally coupled to a monoclonal antibody may be employed, including (but not limited to) radioisotopes, cytotoxic agents, and chemotherapeutic agents. See generally- Monoclonal Antibodies and Cancer Therapy (R. Reisfeld and S. Sell Eds. 1985) (Alan R. Liss Inc. NY) .
  • Therapeutic agents may be coupled to the antibody by direct means or indirect means (e.g., via a chelator) by any suitable technique, such as the lodogen method or with N-succinimidyl - 3 - (tri-n-butylstanyl)benzoate (the "ATE method") , as will be apparent to those skilled in the art. See, e . g. , M. Zalutsky and A. ⁇ arula, Appl . Radiat . Isot . 38, 1051 (1987) .
  • radioisotopes which may be coupled to a therapeutic monoclonal antibody include, but are not limited to, 131 I, 90 Y, 211 At, 212 Bi, 67 Cu, 186 Re, 188 Re, and 212 Pb.
  • chemotherapeutic agents which may be coupled to a therapeutic monoclonal antibody include, but are not limited to, methotrexate.
  • cytotoxic agents which may be coupled to a therapeutic monoclonal antibody include, but are not limited to, ricin (or more particularly the ricin A chain) .
  • monoclonal antibodies per se which are used as therapeutic monoclonal antibodies incorporate those portions of the constant region of an antibody necessary to evoke a therapeutically useful immunological response in the subject being treated.
  • Therapeutic monoclonal antibodies may be provided in lyophylized form in a sterile aseptic container or may be provided in a pharmaceutical formulation in combination with a pharmaceutically acceptable carrier, such as sterile pyrogen-free water or sterile pyrogen-free physiological saline solution.
  • the method disclosed herein may be employed with subjects suspected of having solid or cystic tumors residing in the central nervous system, particularly the brain (e.g., in the cerebellum, or more preferably in the cerebral cortex, including the frontal, parietal, occipital and temporal lobes) .
  • the method disclosed herein may be employed with solid tumors residing in other solid tissue organs, such as liver, kidney, spleen, brain, breast, muscle, and prostate.
  • the tumor may be any tumor, primary or secondary, that expresses tenascin, including (but not limited to) astrocytic tumors, melanomas, breast carcinomas, and Wilm' s tumor.
  • astrocytic tumors as used herein is used in accordance with the World Health Organization Classification Scheme, and includes astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme. See also D. Russell and L. Rubinstein, Pathology of Tumors of the Nervous System, pp. 83-289 (1989) (Williams and Wilkins) .
  • cystic tumors that is, tumors which grow around a fluid-filled cavity, or cyst .
  • cystic tumors include (but are not limited to) cystic astrocytic tumors such as cystic astrocytomas, cystic anaplastic astrocytomas, and cystic glioblastoma multiforme.
  • the antibody will generally be mixed, prior to administration, with a non-toxic, pharmaceutically acceptable carrier substance (e.g. normal saline or phosphate-buffered saline) , and will be administered using any medically appropriate procedure, e.g., intravenous or intra- arterial administration, injection into the cerebrospinal fluid) .
  • a non-toxic, pharmaceutically acceptable carrier substance e.g. normal saline or phosphate-buffered saline
  • any medically appropriate procedure e.g., intravenous or intra- arterial administration, injection into the cerebrospinal fluid
  • intradermal, intracavity, intrathecal or direct administration to the tumor or to an artery supplying the tumor is advantageous.
  • intrathecal administration or injection into the carotid artery are advantageous for therapy of tumors located in the brain.
  • Dosage of the antibody will depend, among other things, on the tumor being treated, the route of administration, the nature of the therapeutic agent employed, and the sensitivity of the tumor to the particular therapeutic agent.
  • the dosage will typically be about 1 to 10 micrograms per Kilogram subject body weight.
  • the dosage to the patient will typically be from 10 mCi to 100, 300 or even 500 mCi. Stated otherwise, where the therapeutic agent is 131 I, the dosage to the patient will typically be from 5,000 Rads to 100,000 Rads (preferably at least 13,000 Rads, or even at least 50,000 Rads) .
  • Doses for other radionuclides are typically selected so that the tumoricidal dose will be equivalent to the foregoing range for 131 I .
  • the antibody can be administered to the subject in a series of more than one administration, and regular periodic administration will sometimes be required.
  • the antibody may be administered by depositing it into the inner cavity of a cystic tumor (i.e., a fluid-filled cavity around which the tumor grows) by any suitable technique, such as by direct injection (aided by stereotaxic positioning of an injection syringe, if necessary) or by placing the tip of an Ommaya reservoir into the cavity and administering the antibody through the Ommaya reservoir.
  • a cystic tumor i.e., a fluid-filled cavity around which the tumor grows
  • the Ommaya reservoir apparatus is known. See, e . g. , F. Beautys and D. Poplack, Am J. Pediatr. Hematol . Oncol . 11, 74, 76 Fig. 1 (1989) .
  • the tumor is a solid tumor
  • the antibody may be administered by first creating a resection cavity in the location of the tumor in the manner described below, and then depositing the antibody in the resection cavity in like manner as with cystic tumors.
  • the procedure differs from an ordinary craniotomy and tumor resection in only a few minor respects.
  • the smallest possible cortical incision is made and the tumor is removed to the greatest extent possible by resection of tissue within the small cortical incision and in the depths of the cortex.
  • a so-called gross total tumor resection is attempted, with the only thing prohibiting gross total resection being the potential impingement upon neurologically active areas such as speech or motor areas that would leave permanent neurologic damage if surgically approached.
  • the cavity is then preferably rinsed with saline until all bleeding is stopped by cauterization.
  • the pia- arachnoid membrane which is the surface membrane lining the brain around the cortical incision, is preferably cauterized to enhance the formation of fibroblastic reaction and scarring in the pia-arachnoid area and any astroglial scarring in the areas of normal brain.
  • the result is the formation of an enclosed, fluid-filled cavity within the brain tissue at the location from which the tumor was removed (i.e., the cavity is surrounded on all sides by the organ tissue) .
  • the enclosed nature of the resection cavity enhances retention and localization of the therapeutic agent to be administered at the desired site.
  • an Ommaya reservoir may then be placed into the cavity with the tip of the catheter as deep as possible in the tumor bed, and the reservoir secured to the bone in accordance with standard techniques.
  • a standard water ⁇ tight dural closure may then be carried out with sutures, as in any other craniotomy.
  • Resection cavities are formed in other solid tissue organs, as described above, by modification of the foregoing techniques which will be apparent to those skilled in the art.
  • EXAMPLE 1 Drug Formulation Drug is formulated as 2 ml of a sterile, pyrogen-free solution that contains 10 mg of monoclonal antibody 81C6 (20-60 mCi iodine-131) , 0.7 to 0.9% sodium chloride, 0-0.6% sodium phosphate, 0.5% albutein, and water.
  • Antibody is conjugated to iodine- 131 by the lodogen method in accordance with known techniques ⁇ see, e . g. , R. Moseley et al . , Br. J. Cancer 62, 637 (1990)) and the drug formulation is prepared within 24 hours of administration to the patient.
  • Recurrent Cystic Glioblastoma Patient A 45 year old adult male with a recurrent cystic glioblastoma was administered 15.2 mCi of 131 I conjugated to 10 mg of monoclonal antibody 81C6 by the lodogen method and formulated as described above through an Ommaya reservoir placed into the recurrent tumor cyst. Clinical and radiographic examination after treatment indicated a complete response.
  • the patient received a second treatment of the administration of 20.0 mCi of 131 I conjugated to 7.9 mg of monoclonal antibody 81C6 by the ATE method and formulated as described above through the Ommaya reservoir approximately 15 months after the first treatment .
  • a 29 year old adult female with a recurrent cystic astrocytoma was administered 21.7 mCi of 131 I conjugated to 10 mg of monoclonal antibody 81C6 by the lodogen method through an Ommaya reservoir placed into the recurrent tumor cyst .
  • Clinical and radiographic examination after treatment indicated a partial response.
  • the patient was still alive 11 months after treatment. This patient is indicated as line 3 in Figure 1.
  • a 14 year old female with a recurrent cystic glioblastoma was administered 20.07 mCi of 131 I conjugated to 10 mg of monoclonal antibody 81C6 by the lodogen method through an Ommaya reservoir placed into the recurrent tumor cyst.
  • Clinical and radiographic examination after treatment indicated progressive disease. The patient survived 4 months beyond treatment. This patient is indicated as line 4 in Figure 1.
  • a cystic resection cavity was surgically created in a 53 year old female patient afflicted with an intracranial glioblastoma.
  • the procedure was carried out in essentially the same manner as an ordinary craniotomy and tumor resection, but differed in a few respects.
  • the smallest possible cortical incision was made and the tumor was removed to the greatest extent possible by resection of tissue within the small cortical incision and in the depths of the cortex.
  • a so-called gross total tumor resection was attempted, with the only thing prohibiting gross total resection being the potential impingement upon neurologically active areas such as speech or motor areas that would leave permanent neurologic damage if surgically approached.
  • the cavity was then rinsed with saline until all bleeding was stopped by cauterization and the pia-arachnoid membrane, which is the surface membrane lining the brain around the cortical incision, was cauterized to enhance the formation of fibroblastic reaction and scarring in the pia-arachnoid area and any astroglial scarring in the areas of normal brain.
  • An Ommaya reservoir was then placed into the cavity with the tip of the catheter as deep as possible in the tumor bed, and the reservoir secured to the bone in accordance with standard techniques. A standard water-tight dural closure was then carried out with sutures.
  • RNA and genomic DNA were isolated from cells using the guanidine isothiocyanate cushion method of ultracentrifugation (J. Chirgwin et al . , Biochemistry 18, 5294 (1979)) as detailed in S. Batra et al . , Cel . Growth Differ. 2, 385 (1991) and S. Batra et al . , J. Biol . Chem . 266, 6830 (1991) . Genomic DNA was further purified by sodium dodecyl sulfate-protenase-K digestion and phenol :chloroform (1:1, v./v) extraction.
  • RNA pellet was resuspended in 0.3 M sodium acetate and precipitated with ethanol .
  • Plasmid DNA was isolated by alkaline lysis and PZ523 columns (5 prime ⁇ 3 prime, Boulder, CO) . DNA was analyzed using standard Southern blotting. After digestion with various restriction endonucleases, DNA fragments were fractionated through 0.8% agarose gel by electrophoresis and transferred to a nitrocellulose or nylon transfer membrane (Scheicher __ Schuell, Keene, NH) . The membrane was then hybridized with [ 32 P] dCTP (ICN Biochemicals, Irvine, CA) -labeled DNA probes to identify the immunoglobulin gene.
  • [ 32 P] dCTP ICN Biochemicals, Irvine, CA
  • the heavy and light chains were detected with pJH-11 and pJK probes, respectively.
  • the pJH-11 probe is a 1.9-kilobase (kb) BamHI-EcoRI fragment of a murine heavy-chain gene that includes the J3 and J4 segments and the enhancer region
  • the pJK probe is a 2.7-kb Hindlll DNA fragment of a murine K-light-chain gene containing Jl-5 segments.
  • RNA from control and transfected cells was fractionated by electrophoresis on a formaldehyde- containing agarose gel and then transferred to nylon membrane under conditions recommended by the supplier (Scheicher & Schuell) .
  • the heavy-chain transcription was detected using an 81C6 heavy-chain-specific 6-kb EcoRI fragment as the probe.
  • the light-chain transcript was defined using an 81C6 light-chain-specific 11-kb Hindlll fragment as the probe.
  • Heavy-chain and light-chain libraries were constructed from size-selected DNA restriction fragments that had been identified as containing putative rearranged variable region genes by Southern blot analysis.
  • genomic DNA was digested with EcoRI and fractionated through agarose gel.
  • the 3- and 6-kb fragments were isolated from agarose gel using the Genclean II kit (Bio 101, Inc., La Jolla, CA ) and then ligated separately into the EcoRI site of the ⁇ -ZAP II vector (Stratagene, La Jolla, CA) .
  • 81C6 DNA was digested with Hindlll, and the 11-kb fragment was cloned into the Hindlll site of the ⁇ -DASH vector (Stratagene) .
  • the packaging reaction was performed in vitro using Gigapack gold packaging extracts according to the manufacturer's instructions (Stratagene) .
  • the libraries were screened with pJH-11 for heavy chains and pJK for light chains.
  • the positive clones were rescued or subcloned and further characterized by DNA sequencing using -oligonucleotide primers that are specific for the ⁇ - heavy-chain and ⁇ -light-chain J-regions and Sequenase Version 2.0 (United States Biochemical, Cleveland, OH) .
  • Double-strand sequencing was employed for sequence analysis, and both sense and antisense strands of DNA were sequenced.
  • Heavy chain-specific primers were synthesized by Biosynthesis (Denton, TX) for each heavy-chain J-region as follows: Jl (5' - CCCGTTTCAGAATGGAATGTGCAG-3' ) (SEQ ID NO:5) , J2 (5'- CTAAGCTGAATAGAAGAGAGAGG-3 ' ) (SEQ ID NO: 6) , J3 (5"- TGGGAGAAGTTAGGACT-3' ) (SEQ ID NO:7) , and J4 (5'- ATAAAGACCTGGAGAGGCC-3' ) (SEQ ID NO: 8) , k -Chain J-region primers were made by Biosynthesis as described by Hoogenboom, et al . , 1990. To complete the 5' terminal sequence and to read the opposite strand, internal 81C8-specific primers were also used. The amino acid sequence was translated from the nucleo
  • the functional, rearranged 81C6 heavy-chain variable region gene was inserted into expression vector pSV2 ⁇ Hgpt-HuG2, which contains a genomic fragment encoding the human IgG2-constant region and the Ecogpt gene providing resistance to mycophenolic acid.
  • the 81C6 light-chain variable region gene was ligated into expression vector pSV184 ⁇ Hneo-HuK, which includes a DNA fragment encoding the human K-constant region and the neo gene giving resistance to G418 (V. Oi and S. Morrison, Biotechniques 4, 214 (1986) .
  • the chimeric heavy-chain and light-chain constructs were separately introduced or cotransfected into SP2/0 cells using a lipofectin reagent (GIBCO/BRL) .
  • the transfected cells were incubated at 37°C in a 5% C02 atmosphere in 1 x zinc option medium for 24 hours and then in medium containing 10% fetal bovine serum. After 48-h incubation, the cells were transferred to a 96-well microtiter plate and grown in selection medium containing G418 and/or mycophenolic acid.
  • the supernatants of drug-resistant cells were screened for anti-tenascin activity by enzyme-linked immunosorbent assay.
  • the plates were washed and incubated with 50 ⁇ l of streptavidin-alkaline phosphatase (BRL) for 1 h at room temperature, rewashed, and then incubated with 100 ⁇ l/per well of phosphatase substrate (Sigma) (4 mg/ml in 10%) diethanolamine, 0.5 mM MgCl 2 ) .
  • the reaction was stopped with 10 mM L-cysteine, and absorbance was read at 405 nm.
  • Radioiodination Purified n81C6 and ch81C6 (IgG2) were labeled with 125 I (Amersham, Arlington Heights, IL) using the Iodo-Gen (Pierce, Rockford, II) in accordance with known techniques (P. Fraker and J. Speck, Biochem . Biophys . Res . Commun . 80, 849 (1978) ) .
  • the labeled antibodies were separated from free radioiodine by passage through a Sephadex G-25 column. Iodinated antibody preparations were greater than 97% in trichloroacetic acid precipitation analysis.
  • the size and homogeneity of radiolabeled antibody were monitored by size exclusion high-performance liquid chromatography in conjunction with a Model 170 flow-through gamma detector (Beckman, Irvine, CA) .
  • Immunoreactivitv and Affinity Determination For the immunoreactivity assay, 50 ng of labeled antibody was incubated overnight in duplicate with different amounts of D-54 MG human glioma xenograft (antigen positive) and normal rat liver (antigen negative) homogenate in 1 ml of 115 mM phosphate buffer containing 1% bovine serum albumin. The specific binding percentage schreib calculated by subtracting the percentage bound to the rat liver homogenate from that bound to the D-54 tumor homogenate.
  • a modified Scatchard analysis was used to measure the binding affinity of labeled ch81C6.
  • Serially diluted 1251-labeled antibody 200 ⁇ l, 1:2 dilution starting from 1600 ng/ml was incubated in 48-well plates overnight at 37°C with the antigen-positive human glioma cell line U-251 MG-C3 fixed in glutaraldehyde and the antigen-negative human osteogenic sarcoma cell line 2T.
  • the cells were washed and solubilized with 2 N NaOH, and the radioactivity was measured with a gamma counter.
  • the data was analyzed in accordance with known techniques (Y.-S. Lee et al., Cancer Res . 48, 559 (1988)) .
  • Genomic DNA from a 81C6 hybridoma; its fusion partner, myeloma P3X63/Ag8.653; and BALB/c mouse liver representative of the mouse germ line were digested with EcoRI, Hindlll and BamHI and subjected to the Southern blot analysis to identify the putative rearranged 81C6 variable region genes.
  • the hybridization pattern using the 32 P-labeled heavy-chain probe pJH-11 revealed that the 3- and 6-kb EcoRI bands, a 1.2-kb Hindlll band, and a 11-kb BairiHl band were unique to the 81C6 hybridoma. These unique bands were considered as the putative rearranged heavy-chain variable region genes.
  • Hybridization using the 3 P-labeled light-chain probe pJK revealed an 11-kb Hindlll band and a 6-kb BamHI band which were found in the 81C6 hybridoma only, and which were most likely the putative rearranged light-chain variable region genes.
  • two genomic libraries were constructed for 3- and 6-kb EcoRI DNA fragments and screened with the mouse heavy-chain probe pJH-11. Positive clones were subjected to nucleotide sequencing. The sequence analysis found that the clone isolated from a 3-kb fragment library was an aberrantly rearranged gene.
  • nucleotide sequence of a positive clone from a 6-kb fragment library is shown in Figure 2A. It had all the features of an intact variable region, including a functional leader sequence, in-frame V-D and D-J junctions, and cysteines 22 and 92, which are necessary for an intrachain disulfide bond.
  • the conserved octanucleotide, ATGCAAAT was found at nucleotide 144, upstream from the 3' end of the first exon.
  • the 81C6 heavy-chain variable region segment was found to rearrange to the J3 segment.
  • the N-terminal amino acid sequence matched the deduced amino acid sequence.
  • FIG. 2B shows the nucleotide sequence for the 81C6 K-chain, which is rearranged to the Jl segment.
  • the deduced amino acid sequence matched the partial sequence obtained using N-terminal sequencing of the purified 81C6 antibody.
  • the 6-kb EcoRI fragment of the cloned 81C6 heavy-chain variable region gene was ligated at the unique EcoRI site in the intron before the first exon in the human IgG2 constant region of the expression vector pSV2 ⁇ Hgpt-HuG2.
  • the 11-kb Hindlll fragment of the cloned 81C6 light-chain variable region gene was inserted into a unique Hindlll site in expression vector pSV184 ⁇ Hneo-HuK, which contained the human K-constant region gene.
  • the chimeric heavy-chain and light-chain constructs were either separately introduced into SP2/0 cells for confirming the orientation of 81C6 variable region genes in the expression vector, or cotransfected into the SP2/0 cells for expressing chimeric antibody.
  • the transfected cells were grown in medium containing G418 and/or mycophenolic acid.
  • Supernatants of cells resistant to both drugs were screened for the presence of antibody activity using human intact tenascin-coated plates and enzyme-linked immunosorbent assay. Thirteen positive transfectomas were obtained from three transfection experiments. Five of them were subcloned twice, expanded in culture, and injected into athymic mice for producing antibody.
  • ch81C6 Genomic DNA was isolated from the transfected and control cells and analyzed by Southern blotting to determine the integration of chimeric constructs into the SP2/0 cell genome (data not shown) . Hybridization bands at 3 , 6, and 6.5 kb were found in n81C6. All untransfected and transfected SP2/0 cells showed both a strong 6-kb and a weak 3.4-kb band, which were considered to be endogenous immunoglobulin genes from the SP2/0 genome. The hybridization signal in SP2/0 cells transfected with the heavy-chain expression vector was identical to that of untransfected SP2/0 cells.
  • transfectomas H3D4A10 and F12D9A2 which showed additional hybridization bands only after digestion with Hindlll or BamHI .
  • hybridization of the light-chain probe to the Hindlll-digested DNA blot showed hybridization bands at 11 and 2.5 kb in n81C6 as expected (data not shown) .
  • Hybridization bands at 6.5 and 2.5 kb were shown in all untransfected and transfected SP2/0 cells; these two bands were considered to be endogenous immunoglobulin genes from the SP2/0 genome.
  • the hybridization pattern of transfected cells with the vector alone was the same as the pattern of untransfected SP2/0 cells. Additional hybridization bands of different sizes were also detected in all transfected cells either with the light-chain chimeric construct alone or with both light- and heavy-chain chimeric constructs.
  • Lanes 4 and 5 show transfected cells with the light-chain chimeric construct alone.
  • the DNA integration signals varied with different transfectomas. The strongest signal here, as with the heavy-chain probe, was also found in transfectoma F9C11A5.
  • Total RNA, purified from the transfected and control cell lines, was separated by agarose/formaldehyde gel electrophoresis, Northern blotted, and probed with a 6-kb heavy-chain variable segment and an 11-kb Hindlll DNA fragment of 81C6 for heavy-chain and light-chain gene expression, respectively.
  • the data showed the expression of heavy-chain mRNA in the untransfected and transfected cells.
  • the same blot was probed with ⁇ -actin cDNA as a control for mRNA quantity and quality (P. Gunning et al., Mol . Cel . Biol . 3, 787 (1983)) .
  • the heavy-chain variable region gene mRNA was detected in n81C6, transfected SP2/0 cells with the expression vector containing the 81C6 heavy chain in sense orientation, and in all transfectomas secreting chimeric 81C6. But no signal was found in untransfected SP2/0 cells, transfected cells with expression vector alone, or transfected cells with the expression vector carrying the 81C6 heavy chain in antisense orientation.
  • Light-chain mRNA was detected in n81C6, transfected SP2/0 cells with the expression vector containing the 81C6 light-chain variable region gene (SEQ ID NO:2) in sense orientation, and all transfectomas secreting chimeric antibody. There was no hybridization signal found in untransfected SP2/0, transfected cells with the light-chain expression vector alone, and in cells with the expression vector containing the 81C6 light chain in antisense orientation. Strong expression signals of both heavy- and light-chain mRNA were detected in the transfectoma F9C11A5.
  • Chimeric 81C6 antibody was purified from cultured supernatants and ascites by protein A-Sepharose chromatography. The production levels of five transfectomas in supernatant and in ascites are presented in Table 1. High antibody production was obtained from the supernatants and ascites of transfectoma F9C11A5, which had multiple copies of integration of heavy- and light-chain chimeric constructs and high levels of heavy- and light-chain mRNA expression. . The antibody concentration in transfectoma F9C11A5 ascites was two to six times higher than that of n81C6, which was 2.5 mg/ml ascites in previous purification. Production levels of the four other transfectomas were similar, with the exception of H3D4A10 ascites, which was unusually low.
  • a F9CllA5 transfectoma was further used for production of ch81C6 antibodies, which showed a varied yield of 65 to 13.9 mg/ml of ascites.
  • ch81C6 Characterization of ch81C6.
  • the ch81C6 from high production transfectoma F9C11A5 was purified and further characterized. It was labeled with 125 I using the lodogen method, and the percentage of immunoreactivity was determined by absorption with D-54 MG xenograft homogenate. The affinity constant was defined by Scatchard analysis using binding assay on a tenascin-expressing cell line U-251 MGC-3 as described above. Immunoreactivity of 58% was obtained for 125 I ch81C6, which was comparable to a range of 35-70% for 125 I n81C6 in previous experiments (Y.-S. Lee et al. , Cancer Res . 48, 559 (1988) ; Y.-S.
  • Cross-competition assays were performed on U-251 MG-C3 cells using 125 1 ch81C6 and 125 I n81C6 to determine their binding properties. Less than 10% 125 I ch81C6 binding activity was detected after incubation with unlabeled n81C6 or unlabeled ch81C6. The negative control chimeric IgG2, TPS3.2, did not show significant inhibition. Similar reciprocal inhibition of binding was observed for 125 I n81C6 with unlabeled ch81C6 or unlabeled n81C6, but not with negative control murine IgG2b 45.6.
  • MOLECULE TYPE DNA (genomic)
  • GAG AAC ⁇ c AAA GGC AAG GCC ACA CTG ACT TCA GAC AGA TCC TCC AGC
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE DNA (genomic)

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Abstract

Procédé de traitement de tumeurs solides et kystiques, consistant à administrer à un sujet atteint d'une tumeur kystique un anticorps apte à se lier à la tenascine en une quantité thérapeutiquement efficace. L'administration s'effectue par dépôt de l'anticorps dans la cavité kystique de la tumeur kystique. Pour les tumeurs solides, on a prévu un procédé consistant, dans un premier temps, à extraire une tumeur solide d'un organe à tissu solide du sujet atteint, plus à former dans ledit organe une cavité de résection fermée à l'endroit d'où l'on a extrait la tumeur solide; et ensuite à administrer au sujet un agent antinéoplasique par dépôt de l'agent antinéoplasique dans la cavité de résection. Selon un mode préféré de réalisation, on utilise l'anticorps monoclonal 81C6 et des anticorps aptes à se lier à l'épitope lié par l'anticorps monoclonal 81C6.
PCT/US1994/002703 1993-03-19 1994-03-14 Procede de traitement de tumeurs a l'aide d'un anticorps apte a se lier a la tenascine WO1994021293A1 (fr)

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